Process for preparing threo-1-p.nitrophenyl-2-acylamino-1, 3-propanediols



United States Patent PROCESS FOR PREPARING THREO-I-RNITRO-PHENYL-2-ACYLAMINO-1,3-PROPANEDIOLS Alberto Vercellone and CarloGiuseppe Alberti, Milan,

Italy, assignors to Farmaceutici Italia S. A., a corporation of Italy 1No brawing. Application August 29, 1951, Serial No. 244,273

Claims priority, application Italy January 12, 1951 4 Claims. (Cl.260-562) The N acyl derivatives of threo l p.nitrophenyl2-acylamino-1,3-propanediols are substances .of chemical andpharmaceutical interest, in particular D-(-)- threo 1 p.nitrophenyl 2dichloroacetamino 1,3 propanediol, or chloramphenicol which is aWell-known antibiotic active against the microorganisms answerable fortyphoid fevers, and active as well against gram-positive andgram-negative bacteria,

The copending U. 8. application, Serial No. 244,271, claims a new way ofsynthesis of threo-l-p.-nitrophenyl- 2-amino-l,3 -propanediol, based onthe migration N- O of the acyl. group in N,O-diacylated1-pheny1-2-amino- 1,3-propanediols, as obtained,- for example, with$0012 or PC15, and on the subsequent nitration of the 0,0-diacylhydrochlorides thus obtained, followed by the hydrolysis of the acylgroups.

It has now been found that in the case of three-derivatives saidmigration can be obtained also by means of treatment with solutions ofhydrochloric acid in an anhydrous solvent and that if the 0,0-diacylderivatives thus obtained are brought to a pH higher than 7, there takesplace a migration in the opposed sense,

whereby the N,O-diacyl derivatives are obtained again if the pH iscomprised between v7 and 8, while at a pH higher than 8 partialsaponification takes place, which brings about the N-monoac'ylderivatives. From these findings has arisen the process according to thepresent invention for preparing threo 1 p.nitropheny1 2acylamino-LS-propanediols,in particular the N-dichloroacetyl derivative,which as said olfers special therapeutic interest.

The term"acyl, as-used herein, includes lower aliphatic acyl ,andhalogen substituted lower aliphatic acyl radicals.

- According to the present invention, threo-l-phenyl-Z-acylamino-3-acyloxy-propan-l-ols are first transformed into thecorresponding threo-l-phenyl-1,3-diacyloxy-2- aminopropanehydrochlorides by means of treatment with hydrochloric acid dissolved inan anhydrous solvent (methanol, ethanol, ethyl ether, dioxane, acetone,acetic acid etc.) at a temperature between 0 and 30 C. and then the0,0-diacyl hydrochlorides thus obtained are nitrated at a temperaturelower than 0 C. with fuming nitric acid or with mixed acid, both freefrom nitrous acid, whereafter the p.nitro-derivatives thus obtained aresubjected to the migration of an acyl group to the N- position and tothe contemporaneous alkaline saponification of the single acyl groupthat remained in the O- position.

In particular, according to the invention said partial s'aponificationand migration may be effected direct on the previously diluted nitrationmixture, or after separating the diacyl nitro-derivative, by alkalizingto a pH higher than 8, at a temperature comprised between 0 and 40 C.,if needed in the presence of an organic solvent miscible with water,such as an alcohol and a keume are-added and left at rest one night.

, ized and the acetone is evaporated in vacuo; thus the 2,744,135Patented May 1,

"ice

R, R'=alkyl,haloa1kyl (equal or different).

As threo-l-phenyl-2-amino-1,3-propanediol and its dey rivatives containtwo asymmetric carbon atoms, they can exist in the racemic, levogyrateand dextrogyrate forms; it is understood, therefore, that in the presentspecification and. appended claims, it not statedotherwise, both theracemic product and the levogyrate .or

dextrogyrate forms are referred to.

Some examples or embodiment of vthe invention are given hereinafter byway of illustration but not by way of limitation.

Example 1 50 g. of threo-l-phenyl-2-amino-1,3-propanediol N,O- diacetateare dissolved in 200 cm. of anhydrous ethanol and 50 cm. of anhydrousdioxane 35 cm. of gaseous HCldissolved in anhydrous ethanol 30% by vol-After diluting with 1000 carof ether, the hydrochloride of three-1-phenyl-1,3-diacetoxy-Z-aminopropane obtained, M. P. 164-165" C., isfiltered off. The analysis of the compound gives C=54.38%.

50 grams of said hydrochloride are added in small portions to 500 g. offuming nitric acid free from nitrons acid, keeping the temperature at 10C. After 15 the mass is poured into 1500 g. of ice, is alkalized withsodium carbonate to a pH between 7 and 8 and is extracted with ethylacetate. By evaporation of the solution, the .threo-1p.nitrophenyl-Z-acetamino-3-acetoxypropan-l-ol crystallizes; it is thenre-crystallized from the same solvent (M. P. l62163).

50 g. of said compound are dissolved in 700 cm}? of acetone, cooled downto 0 C., then 250 cm. of normal sodium hydroxide are hoursatO" C. p 1

The excess of sodium hydroxide is accurately neutraladdedand it is leftat rest for two 3 three 1 p.nitrophenyl 2 acetamino 1,3 propanediol, M.P. 164-165 C., crystallizes.

Example 2 50 g. ofthreo-1-phenyl-2-dichloroacetamino-3-dichloroacetoxypropan-l-ol aredissolved in 60 cm. of anhydrous dioxane; 400 cm. of anhydrous ether areadded and then 50 cm. of gaseous HCl dissolved in anhydrous ether 15% byvolume. After six 'hours, the hydrochloride ofthreo-l-phenyl-1,3-dichloroacetoxy-2-aminopropane is filtered off andrecrystallized from ethanol. M. P. 159160 C.

50 g. of said hydrochloride are nitrated as in Examplc l; the nitrationmixture is poured into 2500 g. of ice and, while keeping the temperatureat C., it is brought to a pH=l0 with sodium hydroxide; it is dilutedwith acetone until dissolving and is kept at 0 C. for some hours.Subsequently it is neutralized with hydrochloric acid, the acetone isevaporated in vacuo, and the product is extracted with ethyl acetate andcrystallized from the solution; it isthreo-1-p.nitrophenyl-2-dichloroacetamino-1,3-propanediol, which ifre-crystallized from water melts at 149-150 C.

Example 3 If operating as in Example 2 but with D-threo-lphenyl 2dichloroacetamino 3 dichloroacetoxy propan-l-ol, theD-threo-l-phenyl-1,3-dichloroacetoxy- Z-amino-propane hydrochloride isobtained and then the D threo l p.nitrophenyl 2 dichloroacetamino3-dichloroacetoxy-propan-1-01, M. P.=108110 C., (a) =-|20.1 (ethanol;0:498) and finally the D- threo 1 p.nitrophenyl 2 dichloroacetamino 1,3

propanediol, M. P.=149-150 C., (a) =+I9 (ethanol; c=), (u) 25.5 (ethylacetate).

We claim:

1. A process for preparing threo-l-p-nitrophenyl-Z-acetylamino-l,3-propanediol which comprises reacting a threo 1 phenyl 2acylamino 3 acyloxy propane-l-ol, selected from the group consisting ofthreo-lphenyl-2-acetylamino-3-acetoxy-propane-l-ol and threo-lphenyl 2chloroacetylarnino 3 chloroacetoxy propane-l-ol, with gaseoushydrochloric acid dissolved in an anhydrous organic solvent at atemperature between about 0 and about 30 C., treating the resulting 0,0-diacyl hydrochloride with a nitrating agent of the group consisting offumic nitric acid and mixed nitric and sulphuric acid at a temperaturelower than 0 C., separat- 4 ing the resultingl-p-nitrophenyl-1,3-diacyloxy-2-aminopropane N-nitrate by filtration,alkalizing, at a temperature between 0 to 40 C., to a pH value higherthan 8 and recovering threo-1-p-nitrophenyl-Z-acylamino-1,3-propanediol.

2. A process for preparing threo-l-p-nitrophenyl-Z-acetylamino-1,3-propanediol which comprises reacting a threo 1 phenyl 2acylamino 3 acyloxy propane-l-ol, selected from the group consisting ofthreo-lphenyl-Z-acetylamino-acetoxy-propane-l-ol and threo-lphenyl 2chloroacetylamino 3 chloroacetoxy propane-l-ol, with gaseoushydrochloric acid dissolved in an anhydrous organic solvent at atemperature between about 0 and about 30 C., treating the resulting 0,0-diacyl hydrochloride with a nitrating agent of the group consisting offumic nitric acid and mixed nitric and sulphuric acid at a temperaturelower than 0 C., separating the resultingl-p-nitrophenyl-l,3-diacyloxy-2-aminopropane N-nitrate by filtration,adjusting to a pH value between 7 and 8, separating thethreo-l-p-nitrophenyl- 2-acylamino-3-acyloxy-propane-l-ol thus formed,alkalizing, at a temperature between 0 and 40 C., to a pH value higherthan 8 and recovering threo-l-p-nitrophenyl-2-acylamino-1,3-propanediol.

3. The process according to claim 1, wherein the said threo l phenyl 2acylamino 3 acyloxypropane-l-ol isthreo-l-phenyl-2-amino-1,3-propanediol N,O- diacetate.

4. The process according to claim 1, wherein the said threo l phenyl 2acylamino 3 acyloxy propane 1 01 is threo l phenyl 2 dichloroacetamino3-dichloroacetoxypropane-l-ol.

I References Cited in the file of this patent UNITED STATES PATENTS2,483,384- Crooks et al Oct. 4, 1949 2,483,885 Crooks et al Oct. 4, 19492,538,764 Crooks et al Jan. 23, 1951 2,538,765 Crooks et al. Jan. 23,1951 2,695,309 Carrara Nov, 23, 1954 OTHER REFERENCES Rebstock et al.:JACS, vol. 71 (1949) p. 2461. Controvlis et al.: JACS, vol. 71 (1949) p.2468. Phillips et al.: JACS, vol. 72 (1950) pp. 4920-2l. Phillips etal.: JACS, vol. 69 (1947) pp. 203-04.

1. A PROCESS FOR PREPARING THREO-1-P-NITROPHENYL-2ACETYLAMINO-1,3-PROPANEDIOL WHICH COMPRISES REACTING A THREO - 1 - PHENYL - 2 - ACYLAMINO - 3 - ACYLOXY - PROPANE-1-OL, SELECTED FROM THE GROUP CONSISTING OF THREO-1PHENYL-2-ACETYLAMINO-3-ACETOXY-PROPANE-1-O1 AND THREO-1PHENYL - 2 - CHLOROACETYLAMINO - 3 - CHLOROACETOXY - PROPANE-1-OL, WITH GASEOUS HYDROCHLORIC ACID DISSOLVED IN AN ANHYDROUS ORGANIC SOLVENT AT A TEMPERATURE BETWEEN ABOUT 0 AND ABOUT 30* C., TREATING THE RESULTING O,ODIACYL HYDROCHLORIDE WITH A NITRATING AGENT OF THE GROUP CONSISTING OF FUMIC NITRIC ACID AND MIXED NITRIC AND SULPHURIC ACID AT A TEMPERATURE LOWER THAN 0* C., SEPARATING THE RESULTING 1-P-NITROPHENYL-1,3-DIACYLOXY-2-AMINOPROPANE N-NITRATE BY FILTRATION, ALKALIZING, AT A TEMPERATURE BETWEEN 0 TO 40* C., TO A PH VALUE HIGHER THAN 8 AND RECOVERING THREO-1-P-NITROPHENYL-2-ACYLAMINO-1,3PROPANEDIOL. 